Carcinoembryonic antigen (CEA) is the best characterized human tumor-associated antigen and the most widely used tumor marker for the in vitro diagnosis of human colon cancers. CEA is one of a family of closely related gene products including normal fecal antigen, non-specific cross-reacting antigen, meconium antigen, and biliary glycoprotein. See, for example, Muraro et al. Cancer Research, 45:5769-5780 (1985); and Rodgers Biochim. Biophys. Aca, 695:227-249 (1983).
The development of antigen-specific monoclonal antibodies (MAbs) for in vitro and in vivo diagnosis and therapy has resulted in the production of a MAb which has an affinity constant in the range of 2.6.times.10.sup.10 M.sup.-1 for CEA (U.S. Pat. No. 5,075,432; T84.66 ATCC Accession No. BH 8747) and little or no cross reactivity to other members of the CEA gene family.
Most available MAbs, however, are derived from murine hybridomas. The in vitro application of murine antibodies in immunoassays presents potential problems associated with false positive results which are attributable to the reaction of serum components with murine immunoglobulins. More importantly however, the in vivo application of murine antibodies in human medicine is often limited due to their inherent immunogenicity. The administration of murine antibodies will, in many patients, induce an immune response which results in a gradual decline in the efficacy of the antibodies during multiple dose regimens. The decrease in efficacy is attributable, at least in part, to the rapid clearance from circulation or alteration of pharmacokinetic properties of murine antibodies by the patient's immune response. The immunogenicity associated with murine monoclonal antibodies, therefore, precludes multiple dose administrations over an extended period of time, or even a single administration if there has been prior exposure, and substantially impacts their potential clinical value.
Chimeric antibodies, in which the binding or variable regions of antibodies derived from one species are combined with the constant regions of antibodies derived from a different species, have been constructed by recombinant DNA methodology. See, for example, Sahagen et al., J. Immunol., 137:1066-1074 (1986); Sun et al., Proc. Natl. Acad. Sci. USA, 82:214-218 (1987); Nishimura et al., Cancer Res., 47:999-1005 (1987); and Lie et al. Proc. Natl. Acad. Sci. USA, 84:3439-3443 (1987) which describe chimeric antibodies to tumor-associated antigens. Typically, the variable region of a murine antibody is joined with the constant region of a human antibody. It is expected that, as such, chimeric antibodies are largely human in composition, and will be substantially less immunogenic than murine antibodies. Accordingly, chimeric antibodies are highly desirable for in vivo application.
While the general concept of chimeric antibodies has been described, it is known that the function of antibody molecules is dependent on its three dimensional structure, which in turn is dependent on its primary amino acid structure. Thus, changing the amino acid sequence of an antibody may adversely affect its activity, see for example, Horgan et al., J. Immunology, 149:127-135 (1992). Moreover, a change in the DNA sequence coding for an antibody may affect the ability of the cell containing the DNA sequence to express, secrete or assemble the antibody.
Although chimeric antibodies against tumors have been described, there exists a need for the development of novel chimeric antibodies having specificity for antigens of human CEA.